Comprehensive analysis of coding variants highlights genetic complexity in developmental and epileptic encephalopathy

Atsushi Takata; Mitsuko Nakashima; Hirotomo Saitsu; Takeshi Mizuguchi; Satomi Mitsuhashi; Yukitoshi Takahashi; Nobuhiko Okamoto; Hitoshi Osaka; Kazuyuki Nakamura; Jun Tohyama; Kazuhiro Haginoya; Saoko Takeshita; Ichiro Kuki; Tohru Okanishi; Tomohide Goto; Masayuki Sasaki; Yasunari Sakai; Noriko Miyake; Satoko Miyatake; Naomi Tsuchida; Kazuhiro Iwama; Gaku Minase; Futoshi Sekiguchi; Atsushi Fujita; Eri Imagawa; Eriko Koshimizu; Yuri Uchiyama; Kohei Hamanaka; Chihiro Ohba; Toshiyuki Itai; Hiromi Aoi; Ken Saida; Tomohiro Sakaguchi; Kouhei Den; Rina Takahashi; Hiroko Ikeda; Tokito Yamaguchi; Kazuki Tsukamoto; Shinsaku Yoshitomi; Taikan Oboshi; Katsumi Imai; Tomokazu Kimizu; Yu Kobayashi; Masaya Kubota; Hirofumi Kashii; Shimpei Baba; Mizue Iai; Ryutaro Kira; Munetsugu Hara; Masayasu Ohta; Yohane Miyata; Rie Miyata; Jun ichi Takanashi; Jun Matsui; Kenji Yokochi; Masayuki Shimono; Masano Amamoto; Rumiko Takayama; Shinichi Hirabayashi; Kaori Aiba; Hiroshi Matsumoto; Shin Nabatame; Takashi Shiihara; Mitsuhiro Kato; Naomichi Matsumoto

doi:10.1038/s41467-019-10482-9

Comprehensive analysis of coding variants highlights genetic complexity in developmental and epileptic encephalopathy

Atsushi Takata, Mitsuko Nakashima, Hirotomo Saitsu, Takeshi Mizuguchi, Satomi Mitsuhashi, Yukitoshi Takahashi, Nobuhiko Okamoto, Hitoshi Osaka, Kazuyuki Nakamura, Jun Tohyama, Kazuhiro Haginoya, Saoko Takeshita, Ichiro Kuki, Tohru Okanishi, Tomohide Goto, Masayuki Sasaki, Yasunari Sakai, Noriko Miyake, Satoko Miyatake, Naomi TsuchidaKazuhiro Iwama, Gaku Minase, Futoshi Sekiguchi, Atsushi Fujita, Eri Imagawa, Eriko Koshimizu, Yuri Uchiyama, Kohei Hamanaka, Chihiro Ohba, Toshiyuki Itai, Hiromi Aoi, Ken Saida, Tomohiro Sakaguchi, Kouhei Den, Rina Takahashi, Hiroko Ikeda, Tokito Yamaguchi, Kazuki Tsukamoto, Shinsaku Yoshitomi, Taikan Oboshi, Katsumi Imai, Tomokazu Kimizu, Yu Kobayashi, Masaya Kubota, Hirofumi Kashii, Shimpei Baba, Mizue Iai, Ryutaro Kira, Munetsugu Hara, Masayasu Ohta, Yohane Miyata, Rie Miyata, Jun ichi Takanashi, Jun Matsui, Kenji Yokochi, Masayuki Shimono, Masano Amamoto, Rumiko Takayama, Shinichi Hirabayashi, Kaori Aiba, Hiroshi Matsumoto, Shin Nabatame, Takashi Shiihara, Mitsuhiro Kato, Naomichi Matsumoto

Reproductive and Developmental Medicine

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Abstract

Although there are many known Mendelian genes linked to epileptic or developmental and epileptic encephalopathy (EE/DEE), its genetic architecture is not fully explained. Here, we address this incompleteness by analyzing exomes of 743 EE/DEE cases and 2366 controls. We observe that damaging ultra-rare variants (dURVs) unique to an individual are significantly overrepresented in EE/DEE, both in known EE/DEE genes and the other non-EE/DEE genes. Importantly, enrichment of dURVs in non-EE/DEE genes is significant, even in the subset of cases with diagnostic dURVs (P = 0.000215), suggesting oligogenic contribution of non-EE/DEE gene dURVs. Gene-based analysis identifies exome-wide significant (P = 2.04 × 10⁻⁶) enrichment of damaging de novo mutations in NF1, a gene primarily linked to neurofibromatosis, in infantile spasm. Together with accumulating evidence for roles of oligogenic or modifier variants in severe neurodevelopmental disorders, our results highlight genetic complexity in EE/DEE, and indicate that EE/DEE is not an aggregate of simple Mendelian disorders.

Original language	English
Article number	2506
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-10482-9
Publication status	Published - Dec 1 2019

All Science Journal Classification (ASJC) codes

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/s41467-019-10482-9

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Takata, A., Nakashima, M., Saitsu, H., Mizuguchi, T., Mitsuhashi, S., Takahashi, Y., Okamoto, N., Osaka, H., Nakamura, K., Tohyama, J., Haginoya, K., Takeshita, S., Kuki, I., Okanishi, T., Goto, T., Sasaki, M., Sakai, Y., Miyake, N., Miyatake, S., ... Matsumoto, N. (2019). Comprehensive analysis of coding variants highlights genetic complexity in developmental and epileptic encephalopathy. Nature communications, 10(1), Article 2506. https://doi.org/10.1038/s41467-019-10482-9

Takata, A, Nakashima, M, Saitsu, H, Mizuguchi, T, Mitsuhashi, S, Takahashi, Y, Okamoto, N, Osaka, H, Nakamura, K, Tohyama, J, Haginoya, K, Takeshita, S, Kuki, I, Okanishi, T, Goto, T, Sasaki, M, Sakai, Y, Miyake, N, Miyatake, S, Tsuchida, N, Iwama, K, Minase, G, Sekiguchi, F, Fujita, A, Imagawa, E, Koshimizu, E, Uchiyama, Y, Hamanaka, K, Ohba, C, Itai, T, Aoi, H, Saida, K, Sakaguchi, T, Den, K, Takahashi, R, Ikeda, H, Yamaguchi, T, Tsukamoto, K, Yoshitomi, S, Oboshi, T, Imai, K, Kimizu, T, Kobayashi, Y, Kubota, M, Kashii, H, Baba, S, Iai, M, Kira, R, Hara, M, Ohta, M, Miyata, Y, Miyata, R, Takanashi, JI, Matsui, J, Yokochi, K, Shimono, M, Amamoto, M, Takayama, R, Hirabayashi, S, Aiba, K, Matsumoto, H, Nabatame, S, Shiihara, T, Kato, M & Matsumoto, N 2019, 'Comprehensive analysis of coding variants highlights genetic complexity in developmental and epileptic encephalopathy', Nature communications, vol. 10, no. 1, 2506. https://doi.org/10.1038/s41467-019-10482-9

@article{acacc72c98d94ae89170e2bedc48579d,

title = "Comprehensive analysis of coding variants highlights genetic complexity in developmental and epileptic encephalopathy",

abstract = "Although there are many known Mendelian genes linked to epileptic or developmental and epileptic encephalopathy (EE/DEE), its genetic architecture is not fully explained. Here, we address this incompleteness by analyzing exomes of 743 EE/DEE cases and 2366 controls. We observe that damaging ultra-rare variants (dURVs) unique to an individual are significantly overrepresented in EE/DEE, both in known EE/DEE genes and the other non-EE/DEE genes. Importantly, enrichment of dURVs in non-EE/DEE genes is significant, even in the subset of cases with diagnostic dURVs (P = 0.000215), suggesting oligogenic contribution of non-EE/DEE gene dURVs. Gene-based analysis identifies exome-wide significant (P = 2.04 × 10−6) enrichment of damaging de novo mutations in NF1, a gene primarily linked to neurofibromatosis, in infantile spasm. Together with accumulating evidence for roles of oligogenic or modifier variants in severe neurodevelopmental disorders, our results highlight genetic complexity in EE/DEE, and indicate that EE/DEE is not an aggregate of simple Mendelian disorders.",

author = "Atsushi Takata and Mitsuko Nakashima and Hirotomo Saitsu and Takeshi Mizuguchi and Satomi Mitsuhashi and Yukitoshi Takahashi and Nobuhiko Okamoto and Hitoshi Osaka and Kazuyuki Nakamura and Jun Tohyama and Kazuhiro Haginoya and Saoko Takeshita and Ichiro Kuki and Tohru Okanishi and Tomohide Goto and Masayuki Sasaki and Yasunari Sakai and Noriko Miyake and Satoko Miyatake and Naomi Tsuchida and Kazuhiro Iwama and Gaku Minase and Futoshi Sekiguchi and Atsushi Fujita and Eri Imagawa and Eriko Koshimizu and Yuri Uchiyama and Kohei Hamanaka and Chihiro Ohba and Toshiyuki Itai and Hiromi Aoi and Ken Saida and Tomohiro Sakaguchi and Kouhei Den and Rina Takahashi and Hiroko Ikeda and Tokito Yamaguchi and Kazuki Tsukamoto and Shinsaku Yoshitomi and Taikan Oboshi and Katsumi Imai and Tomokazu Kimizu and Yu Kobayashi and Masaya Kubota and Hirofumi Kashii and Shimpei Baba and Mizue Iai and Ryutaro Kira and Munetsugu Hara and Masayasu Ohta and Yohane Miyata and Rie Miyata and Takanashi, {Jun ichi} and Jun Matsui and Kenji Yokochi and Masayuki Shimono and Masano Amamoto and Rumiko Takayama and Shinichi Hirabayashi and Kaori Aiba and Hiroshi Matsumoto and Shin Nabatame and Takashi Shiihara and Mitsuhiro Kato and Naomichi Matsumoto",

note = "Funding Information: We thank all the study participants and members of the DEEPEN (DEvelopmental and EPileptic ENcephalopathy) Consortium (the full list of consortium members is provided in Supplementary Note 7). This work was supported in part by a grant for Research on Measures for Intractable Diseases, a grant for Comprehensive Research on Disability, Health and Welfare, the Strategic Research Program for Brain Science (SRPBS) from the Japan Agency for Medical Research and Development (AMED) (grant numbers: JP18ek0109280, JP18dm0107090, JP18ek0109301, JP18ek0109348, JP18dm0107133, JP18ek0109381 and JP18kk020500); a Grant-in-Aid for Scientific Research on Innovative Areas (Transcription Cycle) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT); Grants-in-Aid for Scientific Research (A, B, and C), for Young Scientists (A) and for Challenging Exploratory Research from the Japan Society for the Promotion of Science (JSPS) (grant numbers: JP17H01539, JP16H05160, JP16H05357, JP16H06254, JP15K10367, JP17K10080, JP 17K15630 and JP17H06994); the fund for Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program in the Project for Developing Innovation Systems from the Japan Science and Technology Agency (JST); the Takeda Science Foundation; grants from the Ministry of Health, Labour and Welfare of Japan; the Yokohama Foundation for Advancement of Medical Science; the Hayashi Memorial Foundation for Female Natural Scientists; The Ichiro Kanehara Foundation for the Promotion of Medical Science & Medical Care; and The Japan Epilepsy Research Foundation. Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-019-10482-9",

language = "English",

volume = "10",

journal = "Nature communications",

issn = "2041-1723",

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T1 - Comprehensive analysis of coding variants highlights genetic complexity in developmental and epileptic encephalopathy

AU - Takata, Atsushi

AU - Nakashima, Mitsuko

AU - Saitsu, Hirotomo

AU - Mizuguchi, Takeshi

AU - Mitsuhashi, Satomi

AU - Takahashi, Yukitoshi

AU - Okamoto, Nobuhiko

AU - Osaka, Hitoshi

AU - Nakamura, Kazuyuki

AU - Tohyama, Jun

AU - Haginoya, Kazuhiro

AU - Takeshita, Saoko

AU - Kuki, Ichiro

AU - Okanishi, Tohru

AU - Goto, Tomohide

AU - Sasaki, Masayuki

AU - Sakai, Yasunari

AU - Miyake, Noriko

AU - Miyatake, Satoko

AU - Tsuchida, Naomi

AU - Iwama, Kazuhiro

AU - Minase, Gaku

AU - Sekiguchi, Futoshi

AU - Fujita, Atsushi

AU - Imagawa, Eri

AU - Koshimizu, Eriko

AU - Uchiyama, Yuri

AU - Hamanaka, Kohei

AU - Ohba, Chihiro

AU - Itai, Toshiyuki

AU - Aoi, Hiromi

AU - Saida, Ken

AU - Sakaguchi, Tomohiro

AU - Den, Kouhei

AU - Takahashi, Rina

AU - Ikeda, Hiroko

AU - Yamaguchi, Tokito

AU - Tsukamoto, Kazuki

AU - Yoshitomi, Shinsaku

AU - Oboshi, Taikan

AU - Imai, Katsumi

AU - Kimizu, Tomokazu

AU - Kobayashi, Yu

AU - Kubota, Masaya

AU - Kashii, Hirofumi

AU - Baba, Shimpei

AU - Iai, Mizue

AU - Kira, Ryutaro

AU - Hara, Munetsugu

AU - Ohta, Masayasu

AU - Miyata, Yohane

AU - Miyata, Rie

AU - Takanashi, Jun ichi

AU - Matsui, Jun

AU - Yokochi, Kenji

AU - Shimono, Masayuki

AU - Amamoto, Masano

AU - Takayama, Rumiko

AU - Hirabayashi, Shinichi

AU - Aiba, Kaori

AU - Matsumoto, Hiroshi

AU - Nabatame, Shin

AU - Shiihara, Takashi

AU - Kato, Mitsuhiro

AU - Matsumoto, Naomichi

N1 - Funding Information: We thank all the study participants and members of the DEEPEN (DEvelopmental and EPileptic ENcephalopathy) Consortium (the full list of consortium members is provided in Supplementary Note 7). This work was supported in part by a grant for Research on Measures for Intractable Diseases, a grant for Comprehensive Research on Disability, Health and Welfare, the Strategic Research Program for Brain Science (SRPBS) from the Japan Agency for Medical Research and Development (AMED) (grant numbers: JP18ek0109280, JP18dm0107090, JP18ek0109301, JP18ek0109348, JP18dm0107133, JP18ek0109381 and JP18kk020500); a Grant-in-Aid for Scientific Research on Innovative Areas (Transcription Cycle) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT); Grants-in-Aid for Scientific Research (A, B, and C), for Young Scientists (A) and for Challenging Exploratory Research from the Japan Society for the Promotion of Science (JSPS) (grant numbers: JP17H01539, JP16H05160, JP16H05357, JP16H06254, JP15K10367, JP17K10080, JP 17K15630 and JP17H06994); the fund for Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program in the Project for Developing Innovation Systems from the Japan Science and Technology Agency (JST); the Takeda Science Foundation; grants from the Ministry of Health, Labour and Welfare of Japan; the Yokohama Foundation for Advancement of Medical Science; the Hayashi Memorial Foundation for Female Natural Scientists; The Ichiro Kanehara Foundation for the Promotion of Medical Science & Medical Care; and The Japan Epilepsy Research Foundation. Publisher Copyright: © 2019, The Author(s).

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Although there are many known Mendelian genes linked to epileptic or developmental and epileptic encephalopathy (EE/DEE), its genetic architecture is not fully explained. Here, we address this incompleteness by analyzing exomes of 743 EE/DEE cases and 2366 controls. We observe that damaging ultra-rare variants (dURVs) unique to an individual are significantly overrepresented in EE/DEE, both in known EE/DEE genes and the other non-EE/DEE genes. Importantly, enrichment of dURVs in non-EE/DEE genes is significant, even in the subset of cases with diagnostic dURVs (P = 0.000215), suggesting oligogenic contribution of non-EE/DEE gene dURVs. Gene-based analysis identifies exome-wide significant (P = 2.04 × 10−6) enrichment of damaging de novo mutations in NF1, a gene primarily linked to neurofibromatosis, in infantile spasm. Together with accumulating evidence for roles of oligogenic or modifier variants in severe neurodevelopmental disorders, our results highlight genetic complexity in EE/DEE, and indicate that EE/DEE is not an aggregate of simple Mendelian disorders.

AB - Although there are many known Mendelian genes linked to epileptic or developmental and epileptic encephalopathy (EE/DEE), its genetic architecture is not fully explained. Here, we address this incompleteness by analyzing exomes of 743 EE/DEE cases and 2366 controls. We observe that damaging ultra-rare variants (dURVs) unique to an individual are significantly overrepresented in EE/DEE, both in known EE/DEE genes and the other non-EE/DEE genes. Importantly, enrichment of dURVs in non-EE/DEE genes is significant, even in the subset of cases with diagnostic dURVs (P = 0.000215), suggesting oligogenic contribution of non-EE/DEE gene dURVs. Gene-based analysis identifies exome-wide significant (P = 2.04 × 10−6) enrichment of damaging de novo mutations in NF1, a gene primarily linked to neurofibromatosis, in infantile spasm. Together with accumulating evidence for roles of oligogenic or modifier variants in severe neurodevelopmental disorders, our results highlight genetic complexity in EE/DEE, and indicate that EE/DEE is not an aggregate of simple Mendelian disorders.

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JO - Nature communications

JF - Nature communications

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Comprehensive analysis of coding variants highlights genetic complexity in developmental and epileptic encephalopathy

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